Summary In patients presenting with a clinically isolated syndrome, MRI can support and substitute clinical information in the diagnosis of multiple sclerosis by showing disease dissemination in ...space and time and by helping to exclude disorders that can mimic multiple sclerosis. MRI criteria were first included in the diagnostic work-up for multiple sclerosis in 2001, and since then several modifications to the criteria have been proposed in an attempt to simplify lesion-count models for showing disease dissemination in space, change the timing of MRI scanning to show dissemination in time, and increase the value of spinal cord imaging. Since the last update of these criteria, new data on the use of MRI to establish dissemination in space and time have become available, and MRI technology has improved. State-of-the-art MRI findings in these patients were discussed in a MAGNIMS workshop, the goal of which was to provide an evidence-based and expert-opinion consensus on proposed modifications to MRI criteria for the diagnosis of multiple sclerosis.
Abstract B lymphocytes play an important role in the pathogenesis of multiple sclerosis (MS). Follicle-like structures (FLS) have recently been found in the subarachnoid space in the leptomeninges in ...some patients with secondary progressive MS (SPMS). They contain proliferating B lymphocytes, plasma cells, helper T lymphocytes and a network of follicular dendritic cells. FLS have been shown to correlate with increased cortical demyelination, neuronal loss, meningeal infiltration and central nervous system inflammation, as well as lower age at disease onset and progression to severe disability and death. In this review, we will discuss the role of FLS in MS pathogenesis and disease course and the possible influence by B cell activating factor (BAFF) and C-X-C motif chemokine 13 (CXCL13).
Over the last few decades, the improved diagnostic criteria, the wide use of MRI, and the growing availability of effective pharmacologic treatments have led to substantial advances in the management ...of multiple sclerosis (MS). The importance of early diagnosis and treatment is now well-established, but there is still no consensus on how to define and monitor response to MS treatments. In particular, the clinical relevance of the detection of minimal MRI activity is controversial and recommendations on how to define and monitor treatment response are warranted. An expert panel of the Magnetic Resonance Imaging in MS Study Group analyzed and discussed published studies on treatment response in MS. The evolving concept of no evidence of disease activity and its effect on predicting long-term prognosis was examined, including the option of defining a more realistic target for daily clinical practiceminimal evidence of disease activity. Advantages and disadvantages associated with the use of MRI activity alone and quantitative scoring systems combining on-treatment clinical relapses and MRI active lesions to detect treatment response in the real-world setting were also discussed. While most published studies on this topic involved patients treated with interferon-β, special attention was given to more recent studies providing evidence based on treatment with other and more efficacious oral and injectable drugs. Finally, the panel identified future directions to pursue in this research field.
Various inflammatory biomarkers show prognostic potential for multiple sclerosis (MS)-risk after clinically isolated syndromes. However, biomarkers are often examined singly and their interrelation ...and precise aspects of their associated pathological processes remain unclear. Clarification of these relationships could aid the appropriate implementation of prognostic biomarkers in clinical practice.
To investigate the interrelation between biomarkers of inflammation, demyelination and neurodegeneration in acute optic neuritis and to assess their association to measures of MS risk.
A prospective study at a tertiary referral centre from June 2011 to December 2012 of 56 patients with optic neuritis as a first demyelinating symptom and 27 healthy volunteers. Lumbar puncture was performed within 28 (median 16) days of onset. CSF levels of CXCL13, matrix metalloproteinase (MMP)-9, CXCL10, CCL-2, osteopontin and chitinase-3-like-1, myelin basic protein (MBP) and neurofilament light-chain (NF-L) were determined. MS-risk outcome measures were dissemination in space (DIS) of white matter lesions on cerebral MRI, CSF oligoclonal bands and elevated IgG-index.
IN THE INTERRELATION ANALYSIS THE BIOMARKERS SHOWED CLOSE CORRELATIONS WITHIN TWO DISTINCT GROUPS: Biomarkers of leukocyte infiltration (CXCL13, MMP-9 and CXCL10) were strongly associated (p<0.0001 for all). Osteopontin and chitinase-3-like-1 were also tightly associated (p<0.0001) and correlated strongly to tissue damage markers (NF-L and MBP). The biomarkers of leukocyte infiltration all associated strongly with MS-risk parameters, whereas CHI3L1 and MBP correlated with MRI DIS, but not with CSF MS-risk parameters and osteopontin and NF-L did not correlate with any MS-risk parameters.
OUR FINDINGS SUGGEST TWO DISTINCT INFLAMMATORY PROCESSES: one of leukocyte infiltration, represented by CXCL13, CXCL10 and MMP-9, strongly associated with and potentially predicting MS-risk; the other represented by osteopontin and CHI3L1, suggesting tissue damage-related inflammation, potentially predicting residual disabilities after attack and perhaps cumulative damage over time. These hypotheses should be further addressed in follow-up studies.
Summary Background Most patients with multiple sclerosis without previous optic neuritis have thinner retinal layers than healthy controls. We assessed the role of peripapillary retinal nerve fibre ...layer (pRNFL) thickness and macular volume in eyes with no history of optic neuritis as a biomarker of disability worsening in a cohort of patients with multiple sclerosis who had at least one eye without optic neuritis available. Methods In this multicentre, cohort study, we collected data about patients (age ≥16 years old) with clinically isolated syndrome, relapsing-remitting multiple sclerosis, and progressive multiple sclerosis. Patients were recruited from centres in Spain, Italy, France, Germany, Czech Republic, Netherlands, Canada, and the USA, with the first cohort starting in 2008 and the latest cohort starting in 2013. We assessed disability worsening using the Expanded Disability Status Scale (EDSS). The pRNFL thickness and macular volume were assessed once at study entry (baseline) by optical coherence tomography (OCT) and was calculated as the mean value of both eyes without optic neuritis for patients without a history of optic neuritis or the value of the non-optic neuritis eye for patients with previous unilateral optic neuritis. Researchers who did the OCT at baseline were masked to EDSS results and the researchers assessing disability with EDSS were masked to OCT results. We estimated the association of pRNFL thickness or macular volume at baseline in eyes without optic neuritis with the risk of subsequent disability worsening by use of proportional hazards models that included OCT metrics and age, disease duration, disability, presence of previous unilateral optic neuritis, and use of disease-modifying therapies as covariates. Findings 879 patients with clinically isolated syndrome (n=74), relapsing-remitting multiple sclerosis (n=664), or progressive multiple sclerosis (n=141) were included in the primary analyses. Disability worsening occurred in 252 (29%) of 879 patients with multiple sclerosis after a median follow-up of 2·0 years (range 0·5–5 years). Patients with a pRNFL of less than or equal to 87 μm or less than or equal to 88 μm (measured with Spectralis or Cirrus OCT devices) had double the risk of disability worsening at any time after the first and up to the third years of follow-up (hazard ratio 2·06, 95% CI 1·36–3·11; p=0·001), and the risk was increased by nearly four times after the third and up to the fifth years of follow-up (3·81, 1·63–8·91; p=0·002). We did not identify meaningful associations for macular volume. Interpretation Our results provide evidence of the usefulness of monitoring pRNFL thickness by OCT for prediction of the risk of disability worsening with time in patients with multiple sclerosis. Funding Instituto de Salud Carlos III.
Background Leber's hereditary optic neuropathy (LHON) and a multiple sclerosis (MS)-like illness appear to coexist 50 times more frequently than would be expected by chance. This association of LHON ...and MS (LMS) raises an important question about whether there could be a common pathophysiological mechanism involving mitochondrial dysfunction. Objective The primary aim was to define MRI features of LMS and LHON, and to assess the proportions of individuals displaying features typical of MS. Secondarily, we investigated the effect of gender on the risk of developing white matter lesions in the context of LHON. Methods A blinded standardised review of conventional brain MRIs of 30 patients with MS, 31 patients with LHON and 11 patients with LMS was conducted by three independent experts in the field. MS-like MRI features were assessed. Results All patients with LMS and 26% of patients with LHON had white matter lesions. Of these, all patients with LMS and 25% with LHON were found to have an MRI appearance typical of MS. Female patients with LHON had a significantly greater risk of having white matter lesions consistent with MS compared with male patients (relative risk 8.3). Conclusions A blinded review of conventional brain MRIs shows that patients with LMS have a scan appearance indistinguishable from MS. Mitochondrial dysfunction could be a common pathophysiological pathway in the formation of white matter lesions. There appears to be a strong female influence on the radiological appearance as well as clinical development of MS in patients with LHON.
The hippocampus in multiple sclerosis Rocca, Maria A; Barkhof, Frederik; De Luca, John ...
Lancet neurology,
10/2018, Letnik:
17, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Some of the clinical manifestations of multiple sclerosis, such as memory impairment and depression, are, at least partly, related to involvement of the hippocampus. Pathological studies have shown ...extensive demyelination, neuronal damage, and synaptic abnormalities in the hippocampus of patients with multiple sclerosis, and improvements in MRI technology have provided novel ways to assess hippocampal involvement in vivo. It is now accepted that clinical manifestations related to the hippocampus are due not only to focal hippocampal damage, but also to disconnection of the hippocampus from several brain networks. Evidence suggests anatomical and functional subspecialisation of the different hippocampal subfields, resulting in variability between regions in the extent to which damage and repair occur. The hippocampus also has important roles in plasticity and neurogenesis, both of which potentially contribute to functional preservation and restoration. These findings underline the importance of evaluation of the hippocampus not only to improve understanding of the clinical manifestations of multiple sclerosis, but also as a potential future target for treatment.
The inflammatory processes observed in the central nervous system in multiple sclerosis (MS) could damage the endothelium of the cerebral vessels and lead to a dysfunctional regulation of vessel ...tonus and recruitment, potentially impairing cerebrovascular reactivity (CVR) and neurovascular coupling (NVC). Impaired CVR or NVC correlates with declining brain health and potentially plays a causal role in the development of neurodegenerative disease. Therefore, we examined studies on CVR or NVC in MS patients to evaluate the evidence for impaired cerebrovascular function as a contributing disease mechanism in MS. Twenty-three studies were included (12 examined CVR and 11 examined NVC). Six studies found no difference in CVR response between MS patients and healthy controls. Five studies observed reduced CVR in patients. This discrepancy can be because CVR is mainly affected after a long disease duration and therefore is not observed in all patients. All studies used CO
2
as a vasodilating stimulus. The studies on NVC demonstrated diverse results; hence a conclusion that describes all the published observations is difficult to find. Future studies using quantitative techniques and larger study samples are needed to elucidate the discrepancies in the reported results.
Optic neuritis is an acute inflammatory condition that is highly associated with multiple sclerosis. Currently, the best predictor of future development of multiple sclerosis is the number of T2 ...lesions visualized by magnetic resonance imaging. Previous research has found abnormalities in the permeability of the blood-brain barrier in normal-appearing white matter of patients with multiple sclerosis and here, for the first time, we present a study on the capability of blood-brain barrier permeability in predicting conversion from optic neuritis to multiple sclerosis and a direct comparison with cerebrospinal fluid markers of inflammation, cellular trafficking and blood-brain barrier breakdown. To this end, we applied dynamic contrast-enhanced magnetic resonance imaging at 3 T to measure blood-brain barrier permeability in 39 patients with monosymptomatic optic neuritis, all referred for imaging as part of the diagnostic work-up at time of diagnosis. Eighteen healthy controls were included for comparison. Patients had magnetic resonance imaging and lumbar puncture performed within 4 weeks of onset of optic neuritis. Information on multiple sclerosis conversion was acquired from hospital records 2 years after optic neuritis onset. Logistic regression analysis showed that baseline permeability in normal-appearing white matter significantly improved prediction of multiple sclerosis conversion (according to the 2010 revised McDonald diagnostic criteria) within 2 years compared to T2 lesion count alone. There was no correlation between permeability and T2 lesion count. An increase in permeability in normal-appearing white matter of 0.1 ml/100 g/min increased the risk of multiple sclerosis 8.5 times whereas having more than nine T2 lesions increased the risk 52.6 times. Receiver operating characteristic curve analysis of permeability in normal-appearing white matter gave a cut-off of 0.13 ml/100 g/min, which predicted conversion to multiple sclerosis with a sensitivity of 88% and specificity of 72%. We found a significant correlation between permeability and the leucocyte count in cerebrospinal fluid as well as levels of CXCL10 and MMP9 in the cerebrospinal fluid. These findings suggest that blood-brain barrier permeability, as measured by magnetic resonance imaging, may provide novel pathological information as a marker of neuroinflammation related to multiple sclerosis, to some extent reflecting cellular permeability of the blood-brain barrier, whereas T2 lesion count may more reflect the length of the subclinical pre-relapse phase.See Naismith and Cross (doi:10.1093/brain/awv196) for a scientific commentary on this article.
To compare the performance of the 2017 revisions to the McDonald criteria with the 2010 McDonald criteria in establishing multiple sclerosis (MS) diagnosis and predicting prognosis in patients with ...clinically isolated syndrome (CIS) suggestive of MS.
CSF examination and brain and spinal cord MRI obtained ≤5 months from CIS onset and a follow-up brain MRI acquired within 15 months from CIS onset were evaluated in 785 patients with CIS from 9 European centers. Date of second clinical attack and of reaching Expanded Disability Status Scale score (EDSS) ≥3.0, if they occurred, were also collected. Performance of the 2017 and 2010 McDonald criteria for dissemination in space (DIS), dissemination in time (DIT) (including oligoclonal bands assessment), and DIS plus DIT for predicting a second clinical attack (clinically definite MS CDMS) and EDSS ≥3.0 at follow-up was evaluated. Time to MS diagnosis for the different criteria was also estimated.
At follow-up (median 69.1 months), 406/785 patients with CIS developed CDMS. At 36 months, the 2017 DIS plus DIT criteria had higher sensitivity (0.83 vs 0.66), lower specificity (0.39 vs 0.60), and similar area under the curve values (0.61 vs 0.63). Median time to MS diagnosis was shorter with the 2017 vs the 2010 or CDMS criteria (2017 revision, 3.2; 2010 revision, 13.0; CDMS, 58.5 months). The 2 sets of criteria similarly predicted EDSS ≥3.0 milestone. Three periventricular lesions improved specificity in patients ≥45 years.
The 2017 McDonald criteria showed higher sensitivity, lower specificity, and similar accuracy in predicting CDMS compared to 2010 McDonald criteria, while shortening time to diagnosis of MS.
This study provides Class II evidence that the 2017 McDonald Criteria more accurately distinguish CDMS in patients early after a CIS when compared to the 2010 McDonald criteria.
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